This invention relates to methods for treating prostaglandin mediated diseases. More particularly, the compounds are antagonists of the pain and inflammatory effects of E-type prostaglandins. Additionally preferred compounds are included.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E2 (PGE2) exerts allodynia through the EP1 receptor subtype and hyperalgesia through EP2 and EP3 receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects. These compounds have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
In The American Physiological Society (1994, 267, R289-R-294), studies suggest that PGE2-induced hyperthermia in the rat is mediated predominantly through the EP1 receptor. World patent applications WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
A method of treating or preventing a prostaglandin E mediated disease is described which comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I: 
wherein:
R is a group Ar as defined hereinafter;
R1 is hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, X(CH2)pAr, or a methylenedioxy group attached to two adjacent ring carbon atoms;
R2 is xe2x80x94(CH2)xC(O)N(R4)S(O)yR5, xe2x80x94(CH2)xS(O)yN(R4)C(O)R5, xe2x80x94(CH2)xC(O)N(R4)C(O)R5, xe2x80x94(CH2)xS(O)yN(R4)S(O)yR5, xe2x80x94(CH2)xCO2R4, or tetrazol-5-yl optionally substituted by C1-6alkyl;
R3 is X(CH2)pAr or X(CH2)pR4 or a group of formula (a): 
Ar is a group of formula (b) or (c): 
xe2x80x83or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R7 or R8 groups;
A is Cxe2x95x90O or (C(R4)2)m;
each B is independently xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen or C1-10alkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XC1-5alkyl, C1-5alkyl, NO2, tetrazol-5-yl optionally substituted by C1-6alkyl, or R5 is N(R4)2;
R6 is hydrogen, R10, CO2R11, CO2C(R10)2O(CO)XR11, PO3(R11)2, SO2NR11R10, NR11SO2R10, CONR11SO2R10, SO3R11, S(O)qR11, S(O)qN(R11)C(O)R10, S(O)qN(R11)S(O)qR10, C(O)N(R11)C(O)R10, N(R11)C(O)R10, N(R11)2, N(R11)C(O)NR11, P(O)(OR11)R11, CN, xe2x80x94CO2(CH2)mC(O)N(R4)2, C(R10)2N(R11)2, C(O)N(R4)2, OR4 or tetrazolyl optionally substituted by C1-6 alkyl;
R7 and R9 are independently hydrogen, R10, OH, C1-8 alkoxy, S(O)qR10, N(R4) 2, Br, F, I, Cl, CF3, NO2, NHCOR4, R12CO2R11, xe2x80x94Xxe2x80x94R13xe2x80x94Y, xe2x80x94X(CR4)pOR4, S(CH2)pCO2H, (CH2)pXxe2x80x94R13, xe2x80x94X(CH2)pCONR11SO2R10, (CH2)pXCONR11SO2R10 or X(CH2)pR6 wherein each methylene group within xe2x80x94X(CH2)qR6 may be unsubstituted or substituted by one or two xe2x80x94(CH2)pAr groups;
R8 is hydrogen, R10, OH, C1-5alkoxy, S(O)qR10, N(R4)2, Br, F, I, Cl or NHCOR4 wherein the C1-5 alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R10 is hydrogen, Ar, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, all of which may be unsubstituted or substituted by one or more OH,.CH2OH, N(R4)2 or halogen; or R10 is N(R4)2;
R11 is independently hydrogen, C1-10alkyl, C2-10alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, CO2R14, halogen or XC1-5alkyl; or R11 is (CH2)pAr;
R12 is divalent Ar, C1-10alkylene, C1-10alkylidene, C2-10alkenylene, C2-10alkynylene, all of which may be unsubstituted or substituted by one or more of OH, CH2OH, N(R4)2 or halogen;
R13 is a bond, C1-10alkylene, C1-10alkenylene, C1-10alkylidene, C1-10alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, COOH or halogen;
R14 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-7alkynyl;
X is (CH2)p,O, NR4 or S(O)p;
Y is CH3 or X(CH2)pAr;
q is zero, one or two;
p is an integer from 0 to 6;
m is 1, 2 or 3;
n is 1 to 4;
x is 0 to 4;
y is 1 or 2;
the dotted line signifies the optional presence of a bond such that it represents a single or double bond.
In one aspect of the invention, a method of treating or preventing a prostaglandin E mediated disease is described which comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I: 
wherein:
R is a group Ar as defined hereinafter;
R1 is hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, X(CH2)pAr, or a methylenedioxy group attached to two adjacent ring carbon atoms;
R2 is xe2x80x94(CH2)xC(O)N(R4)S(O)yR5, xe2x80x94(CH2)xS(O)yN(R4)C(O)R5, xe2x80x94(CH2)xC(O)N(R4)C(O)R5, xe2x80x94(CH2)xS(O)yN(R4)S(O)yR5, xe2x80x94(CH2)xCO2R4, or tetrazol-5-yl optionally substituted by C1-6alkyl;
R3 is X(CH2)pAr or X(CH2)pR4 or a group of formula (a): 
Ar is a group of formula (b) or (c): 
xe2x80x83or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R7 or R8 groups;
A is Cxe2x95x90O or (C(R4)2)m;
each B is independently xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
R4 is hydrogen or C1-6alkyl;
R5 is hydrogen or C1-10alkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XC1-5alkyl, C1-5alkyl, NO2, tetrazol-5-yl optionally substituted by C1-6alkyl, or R5 is N(R4)2;
R6 is hydrogen, R10, CO2R11, CO2C(R10)2O(CO)XR11, PO3(R11)2, SO2NR11R10, NR11SO2R10, CONR11SO2R10, SO3R11, S(O)qR11, S(O)qN(R11)C(O)R10, S(O)qN(R11)S(O)qR10, C(O)N(R11)C(O)R10, N(R11)C(O)R10, N(R11)2, N(R11)C(O)NR11, P(O)(OR11)R11, CN, xe2x80x94CO2(CH2)mC(O)N(R4)2, C(R10)2N(R11)2, C(O)N(R4)2, OR4 or tetrazolyl optionally substituted by C1-6 alkyl;
R7 and R9 are independently hydrogen, R10, OH, C1-8 alkoxy, S(O)qR10, N(R4)2, Br, F, I, Cl, CF3, NO2, NHCOR4, R12CO2R11, xe2x80x94Xxe2x80x94R13xe2x80x94Y, xe2x80x94X(CR4)pOR4, S(CH2)pCO2H, (CH2)pXxe2x80x94R13, xe2x80x94X(CH2)pCONR11SO2R10, (CH2)pXCONR11SO2R10 or X(CH2)pR6 wherein each methylene group within xe2x80x94X(CH2)qR6 may be unsubstituted or substituted by one or two xe2x80x94(CH2)pAr groups;
R8 is hydrogen, R10, OH, C1-5alkoxy, S(O)qR10, N(R4)2, Br, F, I, Cl or NHCOR4 wherein the C1-5 alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R10 is hydrogen, Ar, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, all of which may be unsubstituted or substituted by one or more OH,.CH2OH, N(R4)2 or halogen; or R10 is N(R4)2;
R11 is independently hydrogen, C1-10alkyl, C2-1alkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, CO2R14, halogen or XC1-5alkyl; or R11 is (CH2)pAr;
R12 is divalent Ar, C1-10alkylene, C1-10alkylidene, C2-10alkenylene, C2-10alkynylene, all of which may be unsubstituted or substituted by one or more of OH, CH2OH, N(R4)2 or halogen;
R13 is a bond, C1-10alkylene, C1-10alkenylene, C1-10alkylidene, C1-10alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R4)2, COOH or halogen;
R14 is hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-7 alkynyl;
X is (CH2)p, O, NR4 or S(O)p;
Y is CH3 or X(CH2)pAr;
q is zero, one or two;
p is an integer from 0 to 6;
m is 1, 2 or 3;
n is 1 to 4;
x is 0 to 4;
y is 1 or 2;
the dotted line signifies the optional presence of a bond such that it represents a single or double bond.
An embodiment of the invention that is of particular interest relates to a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is selected from the group consisting of:
(1) pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases;
(2) cellular neoplastic transformations or metastic tumor growth;
(3) diabetic retinopathy and tumor angiogenesis;
(4) prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, asthma or eosinophil related disorders;
(5) Alzheimer""s disease;
(6) glaucoma;
(7) bone loss;
(8) osteoporosis;
(9) promotion of bone formation;
(10) Paget""s disease;
(11) cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions;
(12) GI bleeding and patients undergoing chemotherapy;
(13) coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems;
(14) kidney disease;
(15) thrombosis;
(16) occlusive vascular disease;
(17) presurgery; and
(18) anti-coagulation.
Another embodiment of the invention is a method of treating or preventing prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the prostaglandin mediated disease is pain, fever or inflammation associated with dysmenorrhea.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with other agents or ingredients.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with another agent or ingredient selected from the group consisting of:
(1) an analgesic selected from acetaminophen, phenacetin, aspirin, a narcotic;
(2) a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug or a conventional nonsteroidal anti-inflammatory drug;
(3) caffeine;
(4) an H2-antagonist;
(5) aluminum or magnesium hydroxide;
(6) simethicone;
(7) a decongestant selected from phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine;
(8) an antiitussive selected from codeine, hydrocodone, caramiphen, carbetapentane and dextramethorphan;
(9) another prostaglandin ligand selected from misoprostol, enprostil, rioprostil, omoprostol and rosaprostol; a diuretic; and
(10) a sedating or non-sedating antihistamine. Examples of COX-2 inhibitors are disclosed in U.S. Pat. Nos. 5,474,995; 5,633,272; and 5,466,823; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, and WO 95/0051.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug or a conventional nonsteroidal anti-inflammatory drug.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a conventional nonsteroidal anti-inflammatory drug selected from the group consisting of: aspirin, ibuprofen, naproxen, and ketoprofen.
Another embodiment of the invention is a method of treating or preventing a prostaglandin mediated disease comprising administering to a mammalian patient in need of such treatment a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease, wherein the compound is co-administered with a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug selected from rofecoxib and celecoxib.
Preferred subsets of compounds and species that are useful for the methods described herein are set forth in WO96/30358, incorporated by reference.
Additional preferred species for use in treating prostaglandin mediated diseases or conditions include the following:

Representative compounds having a sulfonamide group are shown below.

Definitions
The following abbreviations have the indicated meanings:
Ac=acetyl
AIBN=2,2xe2x80x2-azobisisobutyronitrile
Bn=benzyl
DIBAL=diisobutyl aluminum hydride
DIPHOS=1,2-bis(diphenylphosphino)ethane
DMAP=4-(dimethylamino)pyridine
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et3N=triethylamine
EtOAc=ethyl acetate
HBBS=Hanks balanced salt solution
HEPES=N-[2-hydroxyethyl]piperazine-Nxe2x80x2-[2-ethanesulfonic acid]
Hex=hexanes
KHMDS=potassium hexamethyldisilazane
LDA=lithium diisopropylamide
LPS=lipopolysaccharide
m-CPBA=metachloroperbenzoic acid
MES=2-[N-morpholino]ethanesulfonic acid
Ms=methanesulfonyl=mesyl
MsO=methanesulfonate=mesylate
NBS=N-bromosuccinimide
NSAID=non-steroidal anti-inflammatory drug
PCC=pyridinium chlorochromate
PDC=pyridinium dichromate
Ph=phenyl
PPTS=pyridinium p-toluenesulfonate
pTSA=p-toluenesulfonic acid
r.t.=room temperature
rac.=racemic
TLC=thin layer chromatography
Tf=trifluoromethanesulfonyl=triflyl
TfO=trifluoromethanesulfonate=triflate
THF=tetrahydrofuran
TLC=thin layer chromatography
Ts=p-toluenesulfonyl=tosyl
TsO=p-toluenesulfonate=tosylate
C3H5=allyl
Alkyl Group Abbreviations
Me=methyl
Et=ethyl
n-Pr=normal propyl
i-Pr=isopropyl
n-Bu=normal butyl
i-Bu=isobutyl
s-Bu=secondary butyl
t-Bu=tertiary butyl
c-Pr=cyclopropyl
c-Bu=cyclobutyl
c-Pen=cyclopentyl
c-Hex=cyclohexyl
The terms alkyl, alkenyl, and alkynyl mean linear, branched, and cyclic structures and combinations thereof.
The term xe2x80x9calkylxe2x80x9d includes xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d and extends to cover carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, and the like.
xe2x80x9cLower alkylxe2x80x9d includes xe2x80x9clower cycloalkylxe2x80x9d and means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d includes xe2x80x9clower cycloalkylxe2x80x9d and means a hydrocarbon, containing one or more rings of from 3 to 12 carbon atoms, with the hydrocarbon having up to a total of 20 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cyclo-heptyl, aldamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo [4.4.0]decyl, and the like.
xe2x80x9cLower cycloalkylxe2x80x9d means a hydrocarbon containing one or more rings of from 3 to 7 carbon atoms, with the hydrocarbon having up to a total of 7 carbon atoms. Examples of lower cycloalkyl groups are cyclopropyl, cyclopropylmethyl, cyclobutyl, 2-cyclopentylethyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, and the like.
The term xe2x80x9calkenylxe2x80x9d includes xe2x80x9ccycloalkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d and means alkenyl groups of 2 to 20 carbon atoms. Examples of alkenyl groups include allyl, 5-decen-1-yl, 2-dodecen-1-yl, and the like.
xe2x80x9cLower alkenylxe2x80x9d includes xe2x80x9clower cycloalkenylxe2x80x9d and means alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d includes xe2x80x9clower cycloalkenylxe2x80x9d and means alkenyl groups of 3 to 20 carbon atoms, which include a ring of 3 to 12 carbon atoms, and in which the alkenyl double bond may be located anywhere in the structure. Examples of cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl, 2-vinyladamant-1-yl, 5-methylene-dodec-1-yl, and the like.
xe2x80x9cLower cycloalkenylxe2x80x9d means alkenyl groups of 3 to 7 carbon atoms, which include a ring of 3 to 7 carbon atoms and in which the double bond may be located anywhere in the structure. Examples of lower cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl, 2-cyclopentylethen-1-yl, and the like.
The term xe2x80x9calkynylxe2x80x9d includes xe2x80x9ccycloalkynylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d and means alkynyl groups of 2 to 20 carbon atoms. Examples of alkynyl groups are ethynyl, 2-pentadecyn-1-yl, 1-eicosyn-1-yl, and the like.
xe2x80x9cLower alkynylxe2x80x9d includes xe2x80x9clower cycloalkynylxe2x80x9d and means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
xe2x80x9cCycloalkynylxe2x80x9d includes xe2x80x9clower cycloalkynylxe2x80x9d and means alkynyl groups of 5 to 20 carbon atoms, which include a ring of 3 to 20 carbon atoms. The alkynyl triple bond may be located anywhere in the group, with the proviso that if it is within a ring, such a ring must be of 10 members or greater. Examples of cycloalkynyl are cyclododecyn-3-yl, 3-cyclohexyl-1-propyn-1-yl, and the like.
xe2x80x9cLower cycloalkynylxe2x80x9d means alkynyl groups of 5 to 7 carbon atoms which include a ring of 3 to 5 carbon atoms. Examples of lower cycloalkynyl are cyclopropylethynyl, 3-(cyclobutyl)-1-propynyl, and the like.
Halogen includes F, Cl, Br, and I.
It is intended that the definition of any substituent in a particular molecule be independent of its definition elsewhere in the molecule.
Optical Isomersxe2x80x94Diastereomersxe2x80x94Geometric Isomers
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Salts
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromnic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Dose Ranges
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
Pharmaceutical Compositions
For the treatment of any of the prostanoid mediated diseases compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
Utilities
The ability of the compounds of formula I to interact with prostaglandin receptors makes them useful for preventing or reversing undesirable symptoms caused by prostaglandins in a mammalian, especially human subject. This mimicking or antagonism of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: Pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compounds of formula I may also be of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis. Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer""s disease, the treatment of glaucoma, for the prevention of bone loss (treatment of osteoporosis) and for the promotion of bone formation (treatment of fractures) and other bone diseases such as Paget""s disease.
By virtue of its prostanoid or prostanoid antagonist activity, a compound of formula I will prove useful as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAID""S) particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; thrombosis, occlusive vascular diseases; those prior to surgery or taking anti-coagulants. Compounds of formula I will also be useful as a cytoprotective agent for patients under chemotherapy.
Combinations with Other Drugs
Compounds of formula I will be useful as a partial or complete substitute for conventional antiinflammatory or analgesic compounds in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating prostaglandin E2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a COX-2 selective inhibiting agent; a conventional NSAID; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; another prostaglandin ligand including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating or non-sedating antihistamine. In addition, the invention encompasses a method of treating prostaglandin E2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
Methods of Synthesis
Compounds of the present invention can be prepared according to the general synthesis schemes appearing in WO96/30358, or in accordance with U.S. Pat. No. 5,391,817, incorporated herein by reference in its entirety. Alternativley, the compounds can be synthesized using the following methods:
Method A
This method make use of Z precursor containing protected acid unit (AC(O)B). Suzuki""s cross coupling between excess aryl dihalide of type 1 and an appropriate boronic acid 2 led to the biaryl 3. In most cases, Pd(PPh3)4 is used as the catalyst, Na2CO3 or CsF as the base in a refluxing mixture of DME/H2O (4/1). A second Suzuki""s coupling between 3 and the boronate 4 followed by acidic hydrolysis of the resulting ester 5 (basic hydrolysis in the cases of methyl or ethyl ester) afforded the desired acid 6. A second strategy involves the formation of the boronic acid 7 from the corresponding halide 3 and a subsequent Suzuki""s coupling with the aryl halide 8. Deprotection of the resulting ester 9 followed by coupling with an appropriate sulfonamide using EDCI/DMAP led to the acyl-sulfonamide 10. 
Method B
In this method the acid group (AC(O)B) is introduce by Horner-Emmons (or Wittig) condensation. Suzuki""s coupling between the boronic acid 11 and the aryl dihalide 1 led to the aldehyde 12 under previously described conditions. The acid unit is introduce by a Horner-Emmons reaction to afford the diaryl halide 13 followed by cross coupling with the boronic acid 1 to give the desired ester 9. Alternatively, coupling between 12 and 2 followed by a Horner-Emmons reaction on the resulting aldehyde 14, can also afford the ester 9. 
Method C
Upon addition of an alkylating reagent (R-Hal) to the anion of tert-butyl ester 15, generated in presence of a hindered base, monosubstituted (16) esters were obtained. The ester (16) can be further modified as described in method A to give the desired a-substituted acids 17. 
Method D
For the synthesis of compounds in which the central heteroaryl Y is a 2,4-thiazole or a 2,5-thiazole (21, 24) see the procedures described in the following references; Nan""ya, S.; Ishida, H.; Kanie, K; Ito, N.; Butsugan, Y. J. Heterocyclic Chem. 1995, 32, 1299. Zhang, M. Q.; Haemers, A.; Vanden Berghe, D.; Pattyn, S. R.; Bolaert, W. J. Heterocyclic Chem. 1991, 28, 673. Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, P. A. Tetrahedron Lett, 1993, 34, 1901.
Method E
For the synthesis of compounds in which the central heteroaryl Y is a 2,4-oxazole or a 2,5-oxazole (28, 31) see the procedures described in the following references; Huang, W.; Pei, J.; Chen, B.; Pei, W.; Ye, X. Tetrahedron, 1996, 52, 10131. Hammar, W. J.; Rustad, M. A. J. Heterocyclic Chem. 1981, 18, 885. 
Method F
For the synthesis of compounds in which the central heteroaryl Y is a 4,1-imidazole (37) see the procedures described in the following references; Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org. Chem. 1995, 60, 5678. Horne, D. A.; Yakushijin, K.; Bxc3xcchi, G. Heterocycle 1994, 39, 139. For the synthesis of aryllead triacetates see; Barton, D. H.; Finet, J. P.; Donnelly, D. M. X. J. Chem. Soc. Perkin T. 1 1992, 1365.